The HIV field is in a critical period to develop rapidly and evaluate immunogens that build upon findings from the RV144 regimen and to put forth rational new paradigms for protection. Over the past seven years, the HVTN Laboratory Program was a major leader and substantial contributor to understanding vaccine effects and immune correlates in the VaxGen, Step and RV144 efficacy trials. We raised the standards of immune monitoring in clinical trials, consistently providing high quality data in a GCLP setting using validated or standardized assays. When indicated, we rapidly shifted priorities, broadened collaborations and improved assays. Our Laboratory Center proposes to continue the performance of high quality, state-of-the-art laboratory research, which will accelerate the development of a safe and efficacious HIV vaccine. To accomplish this, we will execute protocol-related, validated endpoint laboratory assays and more comprehensive immunologic investigations to provide unambiguous measurements of vaccine immunogenicity (Aim 1). We will improve existing and adopt novel technologies that can enhance our knowledge of ways vaccines prime the immune system (Aim 2). In phase 2b-3 trials, we will determine vaccine efficacy and investigate potential immune correlates and mechanisms of protection through vaccination (Aim 3). We will optimize strategies to assess vaccine-induced mucosal defense against HIV-1 invasion (Aim 4). Combination strategies with vaccines to prevent HIV will be an important direction for the HVTN, and we will investigate how these may alter and improve immune responses (Aim 5). Finally, we will apply our expertise to fill gaps in development of vaccines for other major global health concerns (Aim 6). Headquartered at FHCRC, the Laboratory Center will integrate its activities seamlessly with the HVTN Leadership and Operations Center and the Statistical and Data Management Center, and cooperatively with the DAIDS Vaccine Clinical Branch. Our core laboratories will continue to be based at FHCRC and Duke University, and we will expand laboratory capacity in South Africa as needed to support efficacy studies.